Antifolate + Platinum in Advanced NSCLC

Antifolate + Platinum in Advanced NSCLC

TOKYOA platinum-based regimen including the investigational
antifolate pemetrexed disodium (Alimta) is active and well tolerated
in stage IIIb/IV non-small cell lung cancer (NSCLC), according to the
final results of a phase II trial conducted by the National Cancer
Institute of Canada Clinical Trials Group and presented at the 9th
World Conference on Lung Cancer. The drug may also represent a new
option for patients with mesothelioma.

The multicenter study included 31 patients given Alimta plus
cisplatin (Platinol) in 3-week cycles. There were no complete
responses, but 13 partial responses were externally validated. The
overall response rate was 44.8% for all patients and 45.8% for stage
IV patients.

It is a very well-tolerated regimen, it is convenient in the
outpatient setting, and it deserves comparison to other
regimens, said Frances Shepherd, MD, of Princess Margaret
Hospital, Toronto. One-year survival was a very favorable
49%, she said. Median survival was 8.9 months.

A median of six courses was delivered, which attests to the
tolerability and efficacy of this regimen, Dr. Shepherd said.
Over 164 courses, only one patient experienced grade 4
thrombocytopenia, while 11 patients had grade 3-4 granulocytopenia.
There was a single episode of febrile neutropenia.

Only one patient had grade 3 nausea and vomiting (no grade 4). Two
patients had grade 3 diarrhea, and one had grade 4. One patient
discontinued therapy due to rash. There were two episodes of grade 3
neuromotor toxicity and one grade 2 episode of neurosensory toxicity.
Several cardiovascular events occurred but were not thought to be
related to therapy. Nine patients had minor infectious complications
during therapy.

Antifolates represent one potential new treatment option for NSCLC.
But despite demonstrated activity in a number of studies, they have
not yet gained a solid place in the therapeutic spectrum.

Alimta, a multitargeted antifolate, has produced response rates of up
to 30% as a single agent in NSCLC therapy. It is also being studied
in nonplatinum regimens and specifically with gemcitabine (Gemzar), a
drug that has demonstrated significant activity as a single agent and
in combination with cisplatin.

Mesothelioma may also be amenable to treatment with Alimta plus a
platinum agent. Underway is a single-blind, randomized phase III
clinical trial, known as EMPHACIS, that will compare cisplatin alone
with cisplatin/Alimta in patients with malignant pleural mesothelioma.

These patients do not have a lot of treatment options,
said Richard Gralla, MD, director of clinical research, Herbert
Irving Comprehensive Cancer Center, Columbia University. One
could argue whether any chemotherapy today is truly worth the trouble
in this very difficult disease.

Phase II studies with Alimta in mesothelioma have had a
surprisingly high response rate, Dr. Gralla said. The
first goal of therapy, however, is to ameliorate the diverse symptoms
of this disease, which have a significant negative effect on quality
of life. Accordingly, the EMPHACIS trial is designed to show
differences in both survival and quality of life.I think people
will be as interested in the symptomatic relief as they will be in
the survival differences, he said.